Malaria caused by the Plasmodium family of protozoan parasites inflicts enormous morbidity and mortality in many parts of the globe. The disease is characterized by multiple systemic clinical conditions and fatal organ-related pathologies such as cerebral malaria. Although pro-inflammatory cytokines produced by innate sensing of parasites is important for controlling parasitemia and the development of protective immunity, excessive/dysregulated pro-inflammatory cytokine responses cause cerebral and other organ-related severe malaria. Therefore, detailed information on the host-parasite interactions that trigger innate immune responses and in-depth understanding of processes involved in the development of protective immunity and pathogenesis are essential for developing therapeutics and/or an effective vaccine for malaria. We have previously demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathways differentially regulate pro-inflammatory cytokines such as TNF- and IL-12 and that pro-inflammatory cytokines produced by TLR9/MyD88-mediated signaling play critical roles in the generation of cell-mediated and antibody-mediated protective immunity to malaria. In ongoing studies, we have made several novel observations, including the findings that (i) malaria parasites contain unidentified immunostimulatory protein(s) that induce IL-4 production, and (ii) IL-4 treatment and inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway controls parasitemia and provide protection against cerebral malaria in P. bergehi ANKA-mouse model. Further studies on these novel observations will substantially contribute to our understanding of processes involved in cerebral malaria and other severe malaria pathologies. As such, in this grant application, we propose the following specific aims: (i) characterize parasite protein(s) tha induce IL-4 production by macrophages and DCs or other cell types, (ii) study the mechanisms by which IL-4 controls parasitemia and modulate parasite-induced immune responses and provide protection against cerebral malaria, and (iii) gain insight into the modulation of immune responses upon inhibition of ERK signaling pathway that exhibits protection from mouse cerebral malaria pathogenesis. Our long-term goals are to gain detailed insight into the processes involved in malaria pathogenesis and protective immune responses, and to exploit specific targets for the development of effective immunotherapeutics and/or a vaccine for malaria.